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Effects of Liberal vs Restrictive Transfusion Thresholds on Survival and Neurocognitive Outcomes in Extremely Low-Birth-Weight InfantsThe ETTNO Randomized Clinical Trial

Educational Objective
To understand risk factors for adverse outcomes in extremely low-birth-weight infants.
1 Credit CME
Key Points

Question  Do liberal vs restrictive transfusion strategies in extremely low-birth-weight infants improve survival and neurodevelopmental outcome at 24 months of corrected age?

Findings  In this randomized clinical trial that included 1013 infants with birth weights less than 1000 g, a strategy of liberal blood transfusions compared with restrictive blood transfusions resulted in a composite outcome of death or disability at 24 months of corrected age in 44.4% vs 42.9%, respectively, a difference that was not statistically significant.

Meaning  Among extremely low-birth-weight infants, a liberal blood transfusion strategy did not reduce the likelihood of death or disability at 24 months compared with a restrictive strategy.

Abstract

Importance  Red blood cell transfusions are commonly administered to infants weighing less than 1000 g at birth. Evidence-based transfusion thresholds have not been established. Previous studies have suggested higher rates of cognitive impairment with restrictive transfusion thresholds.

Objective  To compare the effect of liberal vs restrictive red blood cell transfusion strategies on death or disability.

Design, Setting, and Participants  Randomized clinical trial conducted in 36 level III/IV neonatal intensive care units in Europe among 1013 infants with birth weights of 400 g to 999 g at less than 72 hours after birth; enrollment took place between July 14, 2011, and November 14, 2014, and follow-up was completed by January 15, 2018.

Interventions  Infants were randomly assigned to liberal (n = 492) or restrictive (n = 521) red blood cell transfusion thresholds based on infants’ postnatal age and current health state.

Main Outcome and Measures  The primary outcome, measured at 24 months of corrected age, was death or disability, defined as any of cognitive deficit, cerebral palsy, or severe visual or hearing impairment. Secondary outcome measures included individual components of the primary outcome, complications of prematurity, and growth.

Results  Among 1013 patients randomized (median gestational age at birth, 26.3 [interquartile range {IQR}, 24.9-27.6] weeks; 509 [50.2%] females), 928 (91.6%) completed the trial. Among infants in the liberal vs restrictive transfusion thresholds groups, respectively, incidence of any transfusion was 400/492 (81.3%) vs 315/521 (60.5%); median volume transfused was 40 mL (IQR, 16-73 mL) vs 19 mL (IQR, 0-46 mL); and weekly mean hematocrit was 3 percentage points higher with liberal thresholds. Among infants in the liberal vs restrictive thresholds groups, the primary outcome occurred in 200/450 (44.4%) vs 205/478 (42.9%), respectively, for a difference of 1.6% (95% CI, −4.8% to 7.9%; P = .72). Death by 24 months occurred in 38/460 (8.3%) vs 44/491 (9.0%), for a difference of −0.7% (95% CI, −4.3% to 2.9%; P = .70), cognitive deficit was observed in 154/410 (37.6%) vs 148/430 (34.4%), for a difference of 3.2% (95% CI, −3.3% to 9.6%; P = .47), and cerebral palsy occurred in 18/419 (4.3%) vs 25/443 (5.6%), for a difference of −1.3% (95% CI, −4.2% to 1.5%; P = .37), in the liberal vs the restrictive thresholds groups, respectively. In the liberal vs restrictive thresholds groups, necrotizing enterocolitis requiring surgical intervention occurred in 20/492 (4.1%) vs 28/518 (5.4%); bronchopulmonary dysplasia occurred in 130/458 (28.4%) vs 126/485 (26.0%); and treatment for retinopathy of prematurity was required in 41/472 (8.7%) vs 38/492 (7.7%). Growth at follow-up was also not significantly different between groups.

Conclusions and Relevance  Among infants with birth weights of less than 1000 g, a strategy of liberal blood transfusions compared with restrictive transfusions did not reduce the likelihood of death or disability at 24 months of corrected age.

Trial Registration  ClinicalTrials.gov Identifier: NCT01393496

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Article Information

Corresponding Author: Axel R. Franz, MD, Center for Pediatric Clinical Studies, Department of Neonatology, University Children’s Hospital Tübingen, Calwerstrasse 7, 72076 Tübingen, Germany (axel.franz@med.uni-tuebingen.de).

Accepted for Publication: June 2, 2020.

Author Contributions: Dr Franz had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Franz, Bassler, Rüdiger, Thome, Maier, Krägeloh-Mann, Kron, Roll, Poets.

Acquisition, analysis, or interpretation of data: Franz, Engel, Bassler, Thome, Maier, Krägeloh-Mann, Kron, Essers, Bührer, Rellensmann, Rossi, Bittrich, Roll, Höhn, Ehrhardt, Avenarius, Körner, Stein, Buxmann, Vochem, Poets.

Drafting of the manuscript: Franz.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Franz, Kron.

Obtained funding: Franz, Bassler.

Administrative, technical, or material support: Franz, Rüdiger, Maier, Bührer, Roll, Höhn, Ehrhardt, Avenarius, Buxmann, Vochem.

Supervision: Franz, Engel, Bassler, Rüdiger, Kron, Bittrich, Buxmann, Poets.

Conflict of Interest Disclosures: Dr Kron reported receipt of personal fees from AbbVie Inc. Dr Poets reported receipt of speaker honoraria from Masimo Inc and Sentec AG. No other disclosures were reported.

Funding/Support: The trial was funded by German Research Foundation (Deutsche Forschungsgemeinschaft) grants Fr-1455/6-1 and Fr-1455/6-2.

Role of the Funder/Sponsor: The German Research Foundation had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. The funding organization did not have the right to veto publication or to control the decision regarding to which journal the manuscript was submitted.

Group Information: ETTNO Investigators: nonauthor contributions to data collection and analysis: Christian A. Maiwald, MD, Gabriele von Oldershausen, Iris Bergmann, MSc, Michael Raubuch, PhD, Wolfgang Buchenau, MD, Birgit Schuler, MA, Center for Pediatric Clinical Studies, University Children’s Hospital Tübingen, Tübingen, Germany (data management, monitoring, and study coordination); Silvia Sander, Institute for Epidemiology and Medical Biometry, University of Ulm, Ulm, Germany (biometry/analysis programmer); Hans-Ulrich Bucher, MD, University Hospital Zurich, Zurich, Switzerland, Heike Rabe, MD, University of Brighton, Brighton, England, Josef Högel, PhD, University of Ulm, Ulm, Germany (data monitoring committee); Tamam Bakchoul, MD, Sigrid Enkel, MD, Transfusion Medicine, University Hospital Tübingen, Tübingen, Germany (blood bank advisory board). Recruiting hospitals and local investigators contributing to patient recruitment and data collection: Germany: Reinhard Hopfner, MD, Manuel B. Schmid, MD, Steffen Ruess, MD, Helmut D. Hummler, MD, Maria Zernickel (University Hospital Ulm, Ulm); Christof Dame, MD, Christoph Czernik, MD, Lars Garten, MD, Florian Guthmann, MD, Dieter Hüseman, MD, Elisabeth Walch, MD, Jessica Blank (Charité Universitätsmedizin Berlin, Berlin); Esther Rieger-Fackeldey, MD, Claudius Werner, MD, Katja Masjosthusmann, MD, Julia Sandkötter, MD, Isabell Hörnig-Franz, MD (University Hospital Münster, Münster); Thomas Kühn, MD, Michael Emeis, MD, Mikosch Wilke, MD, Henriette Schönemann, MD (Klinikum Neukölln, Berlin); Kathrin Roefke, MD (Helios Klinikum Erfurt, Erfurt); Wolfgang Pielemeier, MD, Patrizia Kutz, MD, Laura Stüwe-Kunz, MD (Vestische Kinder-und Jugendklinik Datteln, Universität Witten/Herdecke, Datteln); Klaus Lohmeier, MD, Renate Richter-Werkle, MD (University Hospital Düsseldorf, Düsseldorf); Lars Klein, MD, Dirk Faas, MD (Department of General Pediatrics and Neonatology, Justus-Liebig-University Giessen, Giessen); Rangmar Goelz, MD, Jörg Arand, MD, Ingo Müller-Hansen, MD, Karen B. Kreutzer, MD, Cornelia Wiechers, MD, Christoph E. Schwarz, MD, Irene Steiner-Wilke (University Children’s Hospital Tübingen, Tübingen); Ralf Böttger, MD, Claudia Jungbluth-Strauch, Janine Heindorf (University Hospital Magdeburg, Magdeburg); Christoph Härtel, MD (Campus Lübeck, University Hospital Schleswig-Holstein, Lübeck); Levente Bejo, MD (Klinikum Links der Weser, Bremen); Britta M. Hüning, MD (Department of Paediatrics I, University Duisburg-Essen, Essen); Rolf Schlößer, MD, Doris Fischer, MD, Antje Allendorf, MD (University Hospital Frankfurt, Frankfurt); Michael Zemlin, MD, Pia Göbert, MD, Susanne Kampmann, MD, Silke Thomsen, Mirjam Wege, Franziska Heinz, Evelyn Grandmontagne (University Hospital Marburg, Marburg); Martin Wagner, MD, Ulrich Pohlmann, MD, Patrick Neuberger, MD, Thomas Strahleck, MD, Marlene Westmeier, MD, Zoubida El Hafid, MD, Iris Kallenberg, MD, Aurelia Giordano (Klinikum Stuttgart, Olgahospital, Stuttgart); Annett Bläser, MD, Corinna Gebauer, MD (University Hospital Leipzig, Leipzig); Jürgen Seidenberg, MD, Jeannette Dege, MD, Birgitt Moed, MD (Universitätsklinik für Kinder-und Jugendmedizin, Klinikum Oldenburg AöR, Oldenburg); Orsolya Genzel-Boroviczény, MD, Stefanie Artmann, MD (University Hospital Munich, Munich); Rainer Burghard, MD, Mechthild Hubert, MD, Susanne Lüttchens, MD (DRK-Kinderklinik Siegen, Siegen); Bettina Bohnhorst, MD, Corinna Peter, MD, Christoph Jacobi, MD (Medizinische Hochschule Hannover, Hannover); Barbara Seipolt, MD, Violeta Cerda Ojinaga, MD, Arite Koch, Beate Walter (University Hospital Carl Gustav Carus, Dresden); Hugo Segerer, MD, Annette Keller-Wackerbauer, MD, Jochen Kittel, MD (Department of Neonatology, University Children’s Hospital Regensburg, KUNO, Regensburg); Norbert Teig, MD, Susanne Wiegand, MD, Almut Weitkämper, MD (St Elisabeth-Hospital, Universitätskinderklinik Bochum, Bochum); Dominique Singer, MD, Sarah Kabisch, MD, Monika Wolf, MD (University Medical Center Hamburg-Eppendorf, Hamburg); Mark Schoberer, MD, Thorsten Orlikowsky, MD, Sonja Trepels-Kottek, MD, Victoria Rotering, MD, Catherine Ley (University Hospital Aachen, Aachen); Gernot Buheitel, MD, Wilfried Schenk, MD, Anne C. Garbe, MD (Klinikum Augsburg, Augsburg); Matthias Heckmann, MD, Hagen Bahlmann, MD (Universitätsmedizin Greifswald, Greifswald); Stefan Schäfer, MD, Holger Schiffmann, MD, Bettina Behring, MD, Tanja Bauer, MD (Klinikum Nürnberg Süd, Nürnberg); Hans-Georg Topf, MD, Patrick Morhart, MD, Regina Trollmann, MD, Michael Schroth, MD (University Hospital Erlangen, Erlangen); Angela Kribs, MD, Sandra Zawatzki, MD (University Hospital Cologne, Cologne); Axel von der Wense, MD, Peter Gudowius, MD (Altonaer Kinderkrankenhaus, Hamburg). Other countries: Jes Reinholdt Petersen, MD, Gitte Veiergang, MD, Gorm Greisen, MD (Rigshospitalet Copenhagen, Copenhagen, Denmark); Ulla Christensen, MD, Tine Brink Henriksen, MD (Aarhus Universitetshospital, Aarhus, Denmark); Tuuli Metsvaht, MD (Tartu University Hospital, Tartu, Estonia); Renáta Polácková, MD (The Medical University Ostrava, Ostrava, Czech Republic).

Data Sharing Statement: See Supplement 3.

Additional Contributions: The ETTNO Investigators thank the children and their families for their participation and support. We are grateful for the support of the staff at all participating hospitals and we acknowledge the contributions of Gitte Veiergang, MD, investigator at the Rigshospitalet, Copenhagen, and Joachim Riethmüller, MD, cochair of the Center for Pediatric Clinical Studies and responsible for monitoring in this trial, University Hospital Tübingen, who died during the course of this study. (Neither received compensation for their contribution.)

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